There has been considerable interest in the mTOR signaling pathway because of its role in many processes that have been implicated in both cancer and metabolic diseases. The mTOR protein is a large serine/threonine kinase that acts as the catalytic subunit of two functionally independent complexes called mTORC1 and mTORC2. The mTORC1 complex also contains the proteins Raptor and mLST8 and is regulated by nutrient availability, such as amino acids and glucose, and growth factor signaling. Many, though not all, of these signals are transduced to mTOR through the small G-protein rheb, which associates with and activates mTORC1 directly. The best-characterized downstream substrates are the AGC kinases S6K1 and S6K2 and the translation initiation inhibitor 4EBP1. Through these components, and possibly additional unidentified targets, mTORC1 broadly controls the rate of protein synthesis, sensitivity to insulin through negative feedback signaling, and ribosome biogenesis. mTORC1 is also the target of the FDA approved drug rapamycin, which inhibits the complex by first associating with the cellular protein FKBP12, and then binding to an mTOR domain known as the FKBP12-rapamycin binding domain (FRB).
The mTORC2 complex also contains mTOR and mLST8, but includes the proteins Rictor and mSIN1 instead of Raptor. Like mTORC1, mTORC2 is activated by insulin and other growth factors that activate the PI3K/PTEN pathway but is not affected by nutrient levels. mTORC2 is generally considered to be insensitive to rapamycin, though this may not be true under some circumstances. This complex was recently shown to phosphorylate the hydrophobic motif of the AGC kinase Akt/PKB, which is a key event in the activation of Akt/PKB kinase activity. Akt/PKB is considered a key regulator of cell proliferation, survival, and nutrient uptake and is thought to be the primary downstream effector of PI3K/PTEN signaling. Akt/PKB is also known to be hyper-activated in a wide variety of cancers, particularly in those in which the tumor suppressor PTEN is inactivated or PI3K is mutationally activated. It is also likely that mTORC2 phosphorylates the analogous site on the AGC kinases SGK1/2/3, which show considerable sequence similarity to Akt/PKB and are known to participate in similar processes. Efforts using cell-based screens to discover mTOR inhibitors are often hampered by difficulties in the unambiguous identification of the inhibited species. Due to the independent functions of mTORC1 and mTORC2 and their biological and medical relevance, it would be useful to find modulators of each of these complexes.